DESCRIPTION: (Applicant's Abstract) While dopamine (DA) appears to be crucial for cocaine reinforcement, its involvement in the loss of control and compulsive administration of cocaine in the cocaine addict is much less clear. Using PET we have shown persistent reductions in striatal DA D2 receptors, which are predominantly located on GABA cells, in cocaine abusers. This finding coupled to GABA's role as an effector for DA led us to postulate that the GABA system participates in cocaine addiction. We hypothesize that chronic cocaine administration leads to disregulation of GABA function, which in turn affects GABA modulation of DA as well as cerebral response to DA stimulation. In this grant we propose to evaluate the GABAergic system in cocaine abusers during withdrawal and detoxification, and the effects of treatment with a GABA enhancing drug. We will assess the GABA system indirectly by monitoring the regional brain metabolic response (measured with 2-deoxy-2[18F]fluoro-D-glucose and PET) to lorazepam, a benzodiazepine drug which enhances GABA activity. We will compare the effects of lorazepam to those of placebo in cocaine abusers (n=30) tested 1-2 weeks and then retested 6-8 weeks after last cocaine use. Normal controls (n=20) will be tested in parallel (years 1-3). In years 4-5 we will evaluate the effects of a 6 week treatment with gamma-vinyl GABA (GVG), a GABAergic enhancing drug, on the brain's response to lorazepam in cocaine abusers (n=30). Our working hypotheses are: (1) Cocaine abusers will have an increased sensitivity to GABAergic stimulation secondary to adaptations from decreased GABA function. This will appear as an enhanced brain metabolic response to lorazepam which will be regionally specific and will remain after detoxification. (2) Treatment with GVG will serve to normalize the GABAergic disregulation and restore the secondary adaptation processes. Hence GVG treatment will decrease the enhanced regional metabolic sensitivity to lorazepam in cocaine abusers. Studies in laboratory animals and pilot work from our laboratory in cocaine abusers support these hypotheses. Furthermore, because in laboratory animals GABA enhancing drugs decrease the reinforcing effects of cocaine and attenuate cocaine-induced increases in DA, findings from these studies are of relevance not only from the perspective of understanding neurochemical substrates of addiction, but also for the development of new treatments for cocaine abuse.